The present invention generally relates to devices used as sample holders and sample preparation devices for characterization of solid-state chemical compounds formed in the devices and more particularly to such devices used for rapid screening of solid form libraries.
As is well known, many organic and inorganic compounds can exist in the solid phase in different states, for example, crystalline, quasi-crystalline, nanocrystalline, and/or amorphous solids. These different solid phases may also exhibit different solid forms. The existence of different solid forms of a compound is important because the physical form of a solid can affect its properties, such as, for example, solubility, water sorption and desorption properties, particle size, hardness, drying characteristics, flow and filterability, compressibility, and density. Different solid forms can have different melting points, spectral properties, and thermodynamic stability. In the field of pharmaceuticals, for example, understanding whether a new chemical entity exists in different solid forms is important. Examples of solid forms of a compound would include different salt forms, cocrystals, polymorphs, solvates, and/or hydrates. Determining the solid form of a compound can include analyzing a solid to ascertain the form of the solid. For example, it may be determined that a solid is crystalline. In another instance, one might determine that the solid form is a multicomponent crystal, otherwise known as a cocrystal, such as a hydrate or solvate. As a further example, if the same chemical compound solidifies into different crystal structures, then that compound is deemed to be polymorphic.
Determining the solid form of a compound is particularly important in the pre-formulation stage of development because in a drug substance, variations in properties associated with different forms can lead to differences in dissolution rate, oral absorption, bioavailability, levels of gastric irritation, toxicology results, and clinical trial results, for example. Ultimately both safety and efficacy are impacted by properties that vary among different solid forms. Accordingly, the importance of screening a compound for solid forms (“screening”) is commonly understood.
Screening may be a function of time and effort, with the quality or results of screening being a function of the number of samples prepared and/or analyzed as well as the quality of preparation and/or analysis underlying those samples. Therefore, it is generally desirable to use numerous experimental parameters during a screen of a compound in order to maximize the number of viable solid forms identified and characterized. This generally requires that a very large number of experiments be performed.
One traditional way to screen a compound to determine whether it exists in multiple solid forms is to use individual glass vials for each experiment. Once the experiment is complete, the sample is then transferred to an appropriate holder and labelled before analysis using techniques such as, for example, X-ray powder diffraction (XRPD) in transmission or reflection mode, Raman spectroscopy including Raman microscopy, infrared spectroscopy (IR) including IR microscopy, near IR, or optical microscopy. One disadvantage associated with this method, however, is the amount of time it takes to prepare each sample, i.e., to put the compound of interest, appropriate solvent, and any other desired component of the experiment into individual vials, and then to transfer it to the appropriate holder, label it, and perform the desired analytical technique or techniques. If a large number of experiments is to be performed, the amount of time required to run a screen with this method may be prohibitive. Another disadvantage is that this method requires a relatively large amount of material for each experiment.
Accordingly, it is known to use a “microtiter plate” or a “microplate,” which is an apparatus comprising a plurality of wells. Each well of a microplate can typically hold in the range of a few to a few hundred or more microliters of liquid. The microplates, which are often made of polystyrene or polypropylene, can be clear or opaque.
Using a microplate, the compound of interest, appropriate solvent if applicable, and any other desired component of the experiment can be disposed in each of the wells. Such microplates, which typically comprise 6, 24, 96, 384, or even 1536 or more wells arranged in an array, thus allow multiple experiments to be run simultaneously. This procedure thus significantly reduces the amount of time required to perform the desired large number of experiments in a screen.
Once the experiments are completed and the solvent, if used, is removed, the samples in the microplate can be analyzed in situ, thereby eliminating the step of transferring the sample to a holder. This also allows for a smaller amount of materials to be used in each experiment. One disadvantage associated with conventional microplates, however, is that when the sample is analyzed, for example by XRPD or Raman spectroscopy including Raman microscopy, the material that the microplate is composed of can interfere with the analysis, for example at the well bottom or microplate bottom (“bottom portion”). This can, for example, produce unwanted spectral interference in or contribution to the analytical data, such as the Raman spectrum or XRPD pattern, which can significantly affect the quality of the data obtained.
In an alternative conventional way of screening a compound, an apparatus can be used which consists of a glass plate that is attached under pressure to a block of material that has thru holes with o-rings or another type of gasket, creating a liquid tight seal between the glass plate and the block with holes. After solids are produced in the apparatus, the solids are scraped to the bottom of the apparatus, and the block with holes and the o-rings are removed, so that the solids remain on the glass plate. There are several disadvantages to this type of apparatus, however, including for example that the solid material sticks to or lodges under the o-rings. Another disadvantage is that with the removal of the block with holes and o-rings, there are unprotected piles of solid on the glass plate with nothing to prohibit cross-contamination of the piles. Additionally, with smaller samples requiring smaller holes in the block, smaller o-rings and gaskets are required. These usually need to be custom manufactured. Finally, the composition of the o-rings needs to be matched to each of the solvents used to prevent degradation of the o-rings and contamination of the samples.
As can be seen, there is a need for a sample holder apparatus that allows for flexibility in sample size and eliminates or decreases cross-contamination between samples or interference by the sample holder with the analysis of the sample. Although not required, in some embodiments it may also be advantageous if such a sample holder could be disposable.
Although the present invention may obviate one or more of the above-mentioned disadvantages, it should be understood that some aspects of the invention might not necessarily obviate one or more of those disadvantages.
In the following description, various aspects and embodiments will become evident. In its broadest sense, the invention could be practiced without having one or more features of these aspects and embodiments. Further, these aspects and embodiments are exemplary. Additional objects and advantages of the invention will be set forth in part in the description which follows, and in part will be obvious from the description, or may be learned by practicing of the invention. The objects and advantages of the invention will be realized and attained by means of the elements and combinations particularly pointed out in the appended claims.